The ventricular action potential (AP) is subserved by an interdependent system of voltage-gated ion channels and pumps that both alter and respond (directly or indirectly) to the dynamic transmembrane potential (Δψ_m(t)) via voltage-dependent state transitions governing inward and outward ion currents. The native dynamic inward-outward current balance is subject to disruption caused by acquired or inherited loss or gain of function in one or more ion channels or pumps. Building on our previous work, we used a modified version of the O′Hara-Rudy (ORd) model of the undiseased human ventricular cardiomyocyte to study the pro-arrhythmic effects of three types of arrhythmia-inducing perturbations in midmyocytes (M cells): 1) Blockade of the human ether-a-go-go related gene (hERG) K⁺ channel introduced via a Markov state binding model. 2) Mutation-induced voltage shifts in hERG channel gating, resulting in faster inactivation or slowed recovery of both phosphorylated and non-phosphorylated forms of the channel (known as LQT2 syndrome). 3) Mutation-induced voltage shifts in Na_v1.5 gating, resulting in slowed late inactivation of the phosphorylated and non-phosphorylated forms of the channel (known as LQT3 syndrome). We studied the relationships between ion current anomalies and AP morphology as a function of cycle length (CL) and perturbation type/level. The results are summarized as follows: 1) AP duration (APD) is governed directly by Kir2.1 activation (IK1), which is delayed when repolarization is slowed by abnormal net inward tipping of the dynamic inward-outward current balance (reflected in decreased d(Δψ_m(t))/dt during the late AP repolarization phase). In the case of hERG blockade by non-trappable compounds, the perturbation level consists of the dynamic fractional occupancy of the channel, which is governed by blocker k_on relative to the rate of channel opening, pharmacokinetic exposure, and k_off (in that order). 2) Arrhythmia progresses from prolonged paced APs → atypical APs (spontaneous and paced) → self-sustaining oscillations. Abrupt transitions between these regimes occur at CL- and perturbation-specific thresholds (denoted as T₁, T₂, and T₃, respectively), whereas intra-regime progression proceeds in a graded fashion toward the subsequent threshold. APD and d(Δψ_m(t))/dt during the late repolarization phase varied significantly across the 200 APs of our simulations near the T₁ threshold at CL = 1/35 min, reflecting increasing instability of the AP generation system. 3) Arrhythmic APs exhibit highly variable cycle-to-cycle morphologies, depending on the perturbation level, type, and phasing between the underlying ion channel states and pacing cycle. 4) Atypical APs may be triggered by typical or atypical depolarizations prior to the T₃ threshold, depending on perturbation type/level and phasing relative to CL: a) APD/CL resides outside of the Goldilocks zone: i) APD/CL → 1 at shorter CL and/or longer APD, resulting in pro-arrhythmic ″collisions″ between successive paced APs (AP_i and AP_j) within a given cardiomyocyte. We studied this scenario at 60 and 80 beats per minute (BPM), equating to CL = 1/60 and 1/80 min. ii) APD/CL < 1 at longer CL results in spontaneous atypical depolarizations within prolonged paced APs at elevated takeoff Δψ_m(t) and increased channel phosphorylation levels. We studied this scenario at CL = 1/35 min. b) APD and d(Δψ_m(t))/dt during the late repolarization phase become increasingly variable over successive APs on approach to the T₁ threshold, which is the possible source of short-long-short sequences observed in the ECG preceding torsades de pointes arrhythmia (TdP). 5) All atypical depolarizations are solely Ca_v1.2 (I_Ca,L)-driven (Δψ_m(t) falls within the Na_v1.5 inactivation window), whereas typical depolarizations are Na_v1.5 (I_Na) + I_Ca,L-driven. Atypical depolarization versus typical repolarization occurrences are determined by the faster of Ca_v1.2 and Kir2.1 (I_K1) activation (where I_K1 becomes increasingly dampened as the minimum Δψ_m(t) drifts above the Kir2.1 activation window). 6) Ca_v1.2 inactivation gates reset to the open position (accompanied by recovery) synchronously with channel closing under control conditions, generating a small I_Ca,L window current in the process. This current grows toward a depolarizing spike when the lag time between recovery and closing grows above a threshold level. 7) APs undergo damped oscillatory Ca_v1.2 recovery/re-inactivation cycles above the T₃ threshold, which are refreshed by subsequent pacing signals (nodal or reentrant in origin).

中文翻译：

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使用未患病的人心室心肌细胞的O'Hara-Rudy模型探查细胞性心律失常

心室动作电位（AP）是由电压门控离子通道的一个相互依赖的系统升任和泵两者ALTER和响应（直接或间接）到动态跨膜电位（Δψ_米（t））的通过电压依赖性状态转换管理内向和外向离子流。固有的动态内向外电流平衡容易受到一个或多个离子通道或泵中获得或继承的功能丧失或获得所引起的干扰。在我们之前的工作的基础上，我们使用未患病的人心室心肌细胞的O'Hara-Rudy（ORd）模型的修改版来研究三种类型的引起心律不齐的扰动对中肌细胞（M细胞）的促心律失常作用： 1）阻断人类以太相关基因（hERG）K ⁺通过马尔可夫状态绑定模型引入的通道。2）hERG通道门控中突变引起的电压偏移，导致通道的磷酸化和非磷酸化形式的失活更快或恢复较慢（称为LQT2综合征）。3）突变引起的Na _v电压漂移1.5选通，导致通道的磷酸化和非磷酸化形式（称为LQT3综合征）的晚期失活减慢。我们研究了离子电流异常与AP形态之间的关系，该关系是周期长度（CL）和微扰类型/水平的函数。结果总结如下：1）AP持续时间（APD）直接由Kir2.1激活（IK1）控制，当动态内向外电流平衡的异常净内向倾斜使复极化减慢时，AP持续时间会延迟（反映为减少d（Δψ_米（t））的过程中后期复极化AP相/ DT）。如果hERG被不可捕获的化合物阻断，则扰动水平由通道的动态占位率组成，这由阻断剂k决定_。相对于通道打开率，药代动力学暴露和k _off（以该顺序）。2）心律失常从长时间的起搏AP→非典型的AP（自发和起搏）→自持振荡发展而来。这些方案之间的突然转变发生在CL特定阈值和扰动特定阈值（分别表示为T ₁，T ₂和T ₃）处，而区域内进程以渐变的方式向随后的阈值进行。APD和d（Δψ_米（T））/期间后期复极化阶段DT在我们模拟的200级的AP显著改变靠近Ť ₁CL = 1/35分钟时的阈值，反映了AP生成系统的不稳定性增加。3）心律不齐的AP表现出高度可变的周期间形态，具体取决于扰动水平，类型以及基础离子通道状态和起搏周期之间的相位。4）非典型AP可能在T ₃阈值之前由典型或非典型去极化触发，具体取决于扰动类型/水平和相对于CL的相位：a）APD / CL位于Goldilocks区之外：i）APD / CL→1在较短的CL和/或较长的APD时，会导致连续起搏的AP（AP _i和AP _j）之间发生心律不齐的“碰撞”）在给定的心肌细胞内。我们以每分钟60和80次节拍（BPM）的速度研究了这种情况，等于CL = 1/60和1/80分钟。ⅱ）APD / CL <1在在升高的起飞Δψ延长节奏的AP内长CL导致自发非典型去极化_米（t）和增加的信道的磷酸化水平。我们在CL = 1/35分钟时研究了这种情况。B）APD和d（Δψ_米（t））的过程中的后期复极化阶段/ dt的日益可变过连续的AP上的方法与T ₁的阈值，这是在ECG观察前述短-长-短序列的可能来源尖锐性心律不齐（TdP）。5）所有非典型去极化是单独的Ca _v 1.2（I_钙，L）驱动（Δψ_米（t）落在Na _v 1.5灭活窗口内），而典型的去极化是Na _v 1.5（I _Na）+ I _Ca，L驱动的。非典型的去极化与典型复极化的发生是通过测定Ca的更快_v 1.2和的Kir2.1（I _K1）活化（其中I _K1变得越来越衰减为最小Δψ_米（t）的漂移的Kir2.1的激活窗口上方）。6）Ca _v 1.2灭活门在控制条件下与通道关闭同步地重置到打开位置（伴随恢复），产生小的I _Ca，L在此过程中的窗口电流。当恢复和关闭之间的滞后时间增长到阈值水平以上时，该电流朝着去极化尖峰增长。7）AP经历了高于T ₃阈值的阻尼振荡Ca _v 1.2恢复/重新灭活循环，随后的起搏信号（原点为结点或折返点）对此进行了刷新。